Four agents under development by the Developmental Therapeutics Program(DTP), NCI received attention during this report period. Flavopiridol(NSC-649890), defined previously as a potent direct inhibitor of cyclin-dependent kinase (CDK)1, was shown to inhibit potently CDK2 and CDK4. Analogs obtained from Hoechst India will be screened for selectivity of inhibitory effect. UCN-01(NSC-638850), originally presented to NCI as an inhibitor of protein kinase C, was actually found to be a potent activator of CDKs 1 and 2, and in T-lymphoblasts the appearance of this activation appeared to correlate with the onset of apoptosis. In addition, UCN-01 blocked the radiation-induced G2 checkpoint, suggesting that it may be a potent regulator of the same checkpoint affected by methylxanthines. Thus, targets in addition to PKC must be considered in the action of UCN-01. AG957(NSC) a lead structure for inhibition of the bcr-abl fusion protein in CML cells, acted to irreversibly modify the target bcr-abl oncoprotein, raising the possibility that the mechanism of inhibition may involve selective alkylation of bcr-abl. Initial evidence of binding of geldanamycin (NSC) and a geldanamycin soluble derivative (NSC) to the amino-terminal portion of the heat shock protein hsp 90 was obtained. Clinical trials commenced with continuous infusion (72hr) flavopiridol, and the first two dose levels were well tolerated with 10-50 nM drug level achieved. UCN-01 was approved by the NCI Decision Network for filing of an IND application.